Pyrimidine derivatives

ABSTRACT

Pyrimidine derivatives of formula (I) and  
                 
 
     the physiologically acceptable salts thereof,  
     where R1, R2, R3, R4, W, X, Y and Z have the meanings given in claim  1,  display a phosphodiesterase V inhibition and can be used for treatment of diseases of the coronary circulatory system and for treatment and/or therapy of potency disorders.

[0001] The invention relates to compounds of the formula I

[0002] in which

[0003] R¹ and R² are each, independently of one another, H, A, OH, OA orHal,

[0004] R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,

[0005] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0006] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms,

[0007] or

[0008] W is H or alkyl having 1, 2, 3 or 4 carbon atoms,

[0009] X is CH or N,

[0010] Y is (CH₂)_(q)—R⁷ or R⁵, R⁶ or R⁹, each of which is unsubstitutedor monosubstituted by (CH₂)_(n)R²⁰,

[0011] Z is O, NH or NA′,

[0012] A′ is alkyl having 1-6 carbon atoms, —CHAr or —CHAr-A″,

[0013] A″ is alkyl having 1-6 carbon atoms,

[0014] R⁵ is linear or branched alkyl having 1-10 carbon atoms, in whichone or two CH₂ groups may be replaced by —CH═CH— groups, —C≡C— groups,—O—, CO, —S—, —SO—, SO₂, —NH— or —NA-,

[0015] R⁶ is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,

[0016] R⁷ is a saturated or unsaturated 5-7-membered heterocyclicradical having 1-4 N, O or S atoms which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by R²⁰, A, Hal or CF₃,

[0017] R⁹ is Ar or (CH₂)_(k)—Ar,

[0018] R¹⁰, R¹¹,

[0019] R¹² and R¹³ are each, independently of one another, H, A, Hal,OA, OH, NH₂, NHA, NA₂ or R²⁰,

[0020] R²⁰ is —COOH, —COOA, —CONH₂, —CONHA, —CONA₂, —CN, tetrazol-5-yl,—S(O)_(m)A, —S(O)_(m)NH₂ or —S(O)_(m)OH,

[0021] A is alkyl or alkenyl having from 1 to 6 carbon atoms, in which1-7 H atoms may be replaced by F,

[0022] Ar is a phenyl radical which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OA, OH, SO₂NH₂, SO₂NHA,SO₂NA₂ or CN,

[0023] Hal is F, Cl, Br or I,

[0024] k and q are each, independently of one another, 0, 1, 2, 3 or 4,

[0025] m is 1 or 2

[0026] and

[0027] n is 0, 1, 2 or 3,

[0028] and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios.

[0029] Pyrimidine derivates are disclosed, for example, in EP 0920431,EP 0934321, WO 99/28325, WO 99/55708, WO 00/78767 and WO 01/21620.

[0030] The invention had the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

[0031] It has been found that the compounds of the formula I and saltsand/or solvates thereof have very valuable pharmacological propertiesand are well tolerated.

[0032] In particular, they exhibit specific inhibition of cGMPphosphodiesterase (PDE V).

[0033] Compared with the compounds from the prior art, the compoundsaccording to the invention have more favourable physical/chemicalproperties. Thus, they have better solubility and are, for example,absorbed better on oral administration.

[0034] Quinazolines having a cGMP phosphodiesterase-inhibiting activityare described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid.37, 2106 (1994).

[0035] The biological activity of the compounds of the formula I can bedetermined by methods as described, for example, in WO 93/06104.

[0036] The affinity of the compounds according to the invention for cGMPand cAMP phosphodiesterase is determined by measuring their IC₅₀ values(concentration of the inhibitor needed to achieve 50% inhibition of theenzyme activity).

[0037] The determinations can be carried out using enzymes isolated byknown methods (for example W. J. Thompson et al., Biochem. 1971, 10,311). The experiments can be carried out using a modified batch methodof W. J. Thompson and M. M. Appleman (Biochem. 1979, 18 5228).

[0038] The carboline derivatives described in U.S. Pat. No. 6,043,252are cGMP-specific PDE (PDE V) inhibitors and are suitable for thetreatment of a multiplicity of diseases.

[0039] The compounds according to the invention are therefore suitablefor the treatment of diseases of the cardiovascular system, inparticular cardiac insufficiency, and for the treatment and/or therapyof potency disorders (erectile dysfunction).

[0040] The compounds according to the invention are furthermore suitablefor the treatment of angina, high blood pressure, pulmonaryhypertension, congestive heart failure, cardiac infarction, chronicobstructive pulmonary disease (COPD), cor pulmonale, dextrocardiacinsufficiency, atherosclerosis, conditions of reduced patency of theheart vessels, peripheral vascular diseases, strokes, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritablebowel syndrome, tumours, renal insufficiency, liver cirrhosis, for thetreatment of female sexual disorders, inflammation, osteoporosis,furthermore for the treatment of malign hypertonia, phaeochromacytoma(catecholamine-producing tumour of the adrenal cortex), in peripheralvascular (occlusion) diseases, vascular diseases, thrombocytopenia,ulcus pepticum (benign intestinal ulcer), peristaltic motion disorders,percutaneous transluminal coronary angioplasty, carotid angioplasty,postoperative stenosis of the coronary bypass, premonitory pains andbenign prostate hyperplasia.

[0041] The use of substituted pyrazolopyrimidinones for the treatment ofimpotence is described, for example, in WO 94/28902.

[0042] The compounds are effective as inhibitors ofphenylephrine-induced contractions in corpus cavernosum preparations ofrabbits.

[0043] This biological action can be demonstrated, for example, by themethod described by F. Holmquist et al. in J. Urol., 150, 1310-1315(1993).

[0044] The inhibition of the contraction demonstrates the effectivenessof the compounds according to the invention for the therapy and/ortreatment of potency disorders.

[0045] Pharmaceutical formulations consisting of other phosphodiesteraseV (PDE V) inhibitors together with a second active ingredient aredescribed in WO 00/15639.

[0046] Other combinations are disclosed in WO 00/15228.

[0047] Pharmaceutical formulations consisting of other phosphodiesteraseV (PDE V) inhibitors together with a prostaglandin or prostaglandinderivative are described in WO 00/15639 and WO 00/15228.

[0048] The use of (other) phosphodiesterase IV or V inhibitors incombination with a prostaglandin or prostaglandin derivative for thelocal treatment of erectile dysfunction is described in WO 99/21558.

[0049] R. T. Schermuly et al. in the American Journal of Respiratory andCritical Care Medicine, 160, 1500-6 (1999), describe the therapeuticpotential of prostaglandin I₂ (PGI₂) in aerosol form with systemic PDEinhibitors, preferably dual-selective PDE III/IV inhibitors, in lowdoses for acute and chronic pulmonary hypertension.

[0050] In Pneumologie (54, Suppl. 1, S42, 2000), R. Schermuly et al.describe the influence of PDE-V inhibition on prostacyclin-inducedvasorelaxation in experimental pulmonary hypertonia.

[0051] Pharmaceutical formulations consisting of other phosphodiesteraseV (PDE V) inhibitors together with calcium antagonists (=calcium channelblockers) are described in WO 00/15639.

[0052] Combinations of PDE V inhibitors with endothelin receptorantagonists are described, for example, in WO 99/64004.

[0053] Pharmaceutical formulations consisting of other phosphodiesteraseV (PDE V) inhibitors together with a nitrate are described in WO00/15228. The known contraindication of administration of nitrates atthe same time as taking of PDE V inhibitors in the indication oferectile dysfunction is described, for example, in WO 00/10542. At thesame time, however, it is disclosed that nitrates can be administered asantianginal agents although phosphodiesterase V inhibitors are used atthe same time for treatment of erectile dysfunction.

[0054] Also described therein are pharmaceutical preparations whichcomprise both a nitrate and a phosphodiesterase inhibitor for use in thetherapy of erectile dysfunction and/or in the therapy of cardiovasculardiseases at the same time as the presence of the respective otherindication.

[0055] The compounds of the formula I can be employed as medicamentactive ingredients in human and veterinary medicine. They canfurthermore be employed as intermediates for the preparation of furthermedicament active ingredients.

[0056] The invention accordingly relates to the compounds of the formulaI and to a process for the preparation of compounds of the formula Iaccording to Claim 1 and salts thereof,

[0057] characterised in that

[0058] a) a compound of the formula II

[0059] in which

[0060] Y, Z, R¹ and R² are as defined in Claim 1,

[0061] and L is Cl, Br, OH, SCH₃ or a reactive esterified OH group,

[0062] is reacted with a compound of the formula III

[0063] in which

[0064] X, W, R¹ and R² are as defined in Claim 1,

[0065] or

[0066] b) a radical X in a compound of the formula I is converted intoanother radical X by, for example, hydrolysing an ester group to a COOHgroup or converting a COOH group into an amide or into a cyano group,and/or in that a compound of the formula I is converted into one of itssalts.

[0067] The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

[0068] The term “pharmaceutically usable derivatives” is taken to mean,for example, the salts of the compounds according to the invention andso-called prodrug compounds.

[0069] The term “prodrug derivatives” is taken to mean compounds of theformula I which have been modified with, for example, alkyl or acylgroups, sugars or oligopeptides and which are rapidly cleaved in theorganism to form the active compounds according to the invention.

[0070] These also include biodegradable polymer derivatives of thecompounds according to the invention, as described, for example, in Int.J. Pharm. 115, 61-67 (1995).

[0071] The invention also relates to mixtures of the compounds of theformula I according to the invention, for example mixtures of twodiastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,1:100 or 1:1000.

[0072] These are particularly preferably mixtures of stereoisomericcompounds.

[0073] Above and below, the radicals and parameters R¹, R², R³, R⁴, W,X, Y, Z and L are as defined for the formulae I, II and III, unlessexpressly stated otherwise.

[0074] A is alkyl having 1-6 carbon atoms.

[0075] In the above formulae, alkyl is preferably unbranched and has 1,2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl,furthermore preferably isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

[0076] A is furthermore alkenyl having 2-6 carbon atoms, for examplevinyl or propenyl.

[0077] A is furthermore a halogenated alkyl radical, such as, forexample, trifluoromethyl.

[0078] A′ is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,—CHAr or —CHAr-A″, where Ar is preferably phenyl.

[0079] A″ is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0080] Hal is preferably F, Cl or Br, but also I.

[0081] X is preferably CH, furthermore N.

[0082] The radicals R¹ and R² may be identical or different and arepreferably located in the 3- or 4-position of the phenyl ring. They are,for example, in each case independently of one another, H, OH, alkyl, F,Cl, Br or I or together are ethyleneoxy, methylenedioxy orethylenedioxy. They are preferably also in each case alkoxy, such as,for example, methoxy, ethoxy or propoxy.

[0083] R¹ is, in particular, 3-H, 3-Cl or 3-methoxy.

[0084] R² is, in particular, 4-H, 4-chloro or 4-methoxy.

[0085] R¹ and R² together are, in particular, —OCH₂O—.

[0086] The heterocyclic ring in R⁷ is preferably 2- or 3-furyl, 2- or3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl,2-methyl-1-imidazol-1-yl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl or pyrazinyl.

[0087] R³ und R⁴ together are preferably —(CH₂)₃—, —(CH₂)₄— or—CH═CH—CH═CH—.

[0088] R⁵ is a linear or branched alkyl radical having 1-10 carbonatoms, where the alkyl radical is preferably, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear orbranched heptyl, octyl, nonyl or decyl.

[0089] R⁵ is furthermore, for example, but-2-enyl or hex-3-enyl.

[0090] Very particular preference is given to methyl, ethyl, propyl orbutyl, in which one CH₂ group is preferably replaced by O.

[0091] R⁶ is cycloalkylalkylene having 5-12 carbon atoms, preferably,for example, cyclopentylmethylene, cyclohexylmethylene,cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.

[0092] R⁶ is alternatively cycloalkyl preferably having 5-7 carbonatoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl orcycloheptyl.

[0093] R⁷ is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzo-dioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

[0094] The heterocyclic radicals may also be partially or fullyhydrogenated. R⁷ can thus, for example, also be 2,3-dihydro-2-, -3-, -4-or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetra-hydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylene-dioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)-phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxo-furanyl.

[0095] R⁷ is very particularly preferably piperidyl, pyrrolidinyl orpiperazinyl.

[0096] R¹⁰, R¹¹, R¹², R¹³ are very particularly preferably H.

[0097] Ar is, for example, unsubstituted phenyl, naphthyl or biphenyl,furthermore preferably phenyl, naphthyl or biphenyl which is, forexample, monosubstituted, disubstituted or trisubstituted by A,fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl,trifluoromethyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, benzyloxy, sulfonamido, methyl-sulfonamido,ethylsulfonamido, propylsulfonamido, butylsulfonamido,dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl,ethoxycarbonyl or aminocarbonyl.

[0098] Ar is very particularly preferably phenyl.

[0099] Throughout the invention, all radicals which occur more than oncemay be identical or different, i.e. are independent of one another.

[0100] Accordingly, the invention relates in particular to the compoundsof the formula I in which at least one of the said radicals has one ofthe preferred meanings indicated above. Some preferred groups ofcompounds may be expressed by the following sub-formulae Ia to In, whichconform to the formula I and in which the radicals not designated ingreater detail are as defined under the formula I but in which

[0101] in Ia X is CH;

[0102] in Ib R⁹ is a phenyl radical which is unsubstituted ormonosubstituted or disubstituted by COOH, COOA, CONH₂, CONA₂, CONHA, CN,NHSO₂A, N(SO₂A)₂ or SO₂A;

[0103] in Ic Y is phenyl, 1-piperidinyl, piperazinyl or cyclohexyl, eachof which is monosubstituted or disubstituted by COOH, COOA or—S(O)_(m)A;

[0104] in Id R³ and Rare each, independently of one another, H, A, OA orHal,

[0105] R¹ and R² together are —O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O,

[0106] Y is phenyl, 1-piperidinyl, piperazinyl or cyclohexyl, each ofwhich is monosubstituted or disubstituted by COOH, COOA or —S(O)_(m)A;

[0107] in Ie R³ and R⁴ together are —(CH₂)₃—, —(CH₂)₄— or —CH═CH—CH═CH—,

[0108] R¹ and R² are each, independently of one another, H, OA or Hal,

[0109] R¹ and R² together are alternatively alkylene containing—CH₂—O—CH₂—,

[0110] Y is phenyl, 1-piperidinyl, piperazinyl or cyclohexyl, each ofwhich is monosubstituted or disubstituted by COOH, COOA or —S(O)_(m)A;

[0111] in If Y is cyclopentylmethylene, cyclohexylmethylene,cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene, each ofwhich is monosubstituted by COOH or COOA;

[0112] in Ig Y is R⁵ or R⁶, each of which is substituted by COOH, COOA,CONH₂, CONA₂, CONHA or —S(O)_(m)A;

[0113] in Ih Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0114] R⁵ is methyl, ethyl, propyl or butyl,

[0115] R⁹ is phenyl or benzyl,

[0116] n is 0 or 1,

[0117] R²⁰ is COOH, COOA, CONH₂, CONA₂, CONHA or —S(O)_(m)A;

[0118] in Ii X is CH,

[0119] Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0120] R⁵ is methyl, ethyl, propyl or butyl,

[0121] R⁹ is phenyl or benzyl,

[0122] n is 0 or 1,

[0123] R²⁰ is COOH or COOA;

[0124] in Ij X is CH,

[0125] Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0126] Z is NH or NHA′,

[0127] R⁵ is methyl, ethyl, propyl or butyl,

[0128] R⁹ is phenyl orbenzyl,

[0129] n is 0 or 1,

[0130] R²⁰ is COOH or COOA;

[0131] in Ik X is CH,

[0132] Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0133] Z is O,

[0134] R⁵ is methyl, ethyl, propyl or butyl,

[0135] R⁹ is phenyl or benzyl,

[0136] n is 0 or 1,

[0137] R²⁰ is COOH or COOA;

[0138] in II X is CH,

[0139] Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0140] Z is NH or NHA′,

[0141] R³ and R⁴ together are alkylene having 3-4 carbon atoms,

[0142] R⁵ is methyl, ethyl, propyl or butyl,

[0143] R⁹ is phenyl or benzyl,

[0144] n is 0 or 1,

[0145] R²⁰ is COOH or COOA;

[0146] in Im X is CH,

[0147] Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰,

[0148] Z is O,

[0149] R³ and R⁴ together are alkylene having 3-4 carbon atoms,

[0150] R⁵ is methyl, ethyl, propyl or butyl,

[0151] R⁹ is phenyl or benzyl,

[0152] n is 0 or 1,

[0153] R²⁰ is COOH or COOA;

[0154] in In R¹ and R² are each, independently of one another, H, A, OH,OA or Hal,

[0155] R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,

[0156] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0157] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms,

[0158] or

[0159]  W is H,

[0160]  X is CH or N,

[0161]  Y is (CH₂)_(q)—R⁷, or R⁵, R⁶ or R⁹, each of which isunsubstituted or monosubstituted by (CH₂)_(n)R²,

[0162]  Z is O, NH or NA′,

[0163]  A′ is alkyl having 1-6 carbon atoms, —CHAr or —CHAr-A″,

[0164]  A″ is alkyl having 1-6 carbon atoms,

[0165]  R⁵ is linear or branched alkyl having 1-10 carbon atoms,

[0166]  R⁶ is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,

[0167]  R⁷ is a saturated or unsaturated, 5-7-membered hetero-cyclicradical having 1-2 N atoms which is unsubstituted or monosubstituted byR²⁰, A, Hal or CF₃,

[0168]  R⁹ is Ar or (CH₂)_(k)—Ar,

[0169]  R¹⁰, R¹¹,

[0170]  R¹² and R¹³ are H,

[0171]  R²⁰ is —COOH, —COOA or —S(O)_(m)A,

[0172]  A is alkyl having from 1 to 6 carbon atoms, in which 1-7 H atomsmay be replaced by F,

[0173]  Ar is phenyl,

[0174]  Hal is F, Cl, Br or I,

[0175]  k and q are each, independently of one another, 0, 1, 2, 3 or 4,

[0176]  m is 1 or 2

[0177]  and

[0178]  n is 0, 1, 2 or 3;

[0179] and physiologically acceptable salts and/or solvates thereof.

[0180] The compounds of the formula I and also the starting materialsfor the preparation thereof are, in addition, prepared by methods knownper se, as described in the literature (for example in the standardworks, such as Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

[0181] In the compounds of the formula II or III, R¹, R² and X have themeanings indicated, in particular the preferred meanings indicated.

[0182] If L is a reactive esterified OH group, this is preferablyalkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy)or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy, furthermore also 2-naphthalenesulfonyloxy).

[0183] The compounds of the formula I can preferably be obtained byreacting compounds of the formula II with compounds of the formula III.

[0184] If desired, the starting materials can also be formed in situ bynot isolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

[0185] On the other hand, it is possible to carry out the reactionstepwise.

[0186] The starting compounds of the formulae II and III are generallyknown. If they are not known, they can be prepared by methods known perse.

[0187] The compounds of the formula II are generally prepared from thecorresponding 2-aminoindole or 2-aminofuran derivatives.

[0188] Compounds of the formula II

[0189] in which

[0190] Z is NH or NHA′,

[0191] L is Cl,

[0192] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0193] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0194] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms,

[0195] and n, R²⁰, R⁵, R⁶ and R⁹ are as defined in Claim 1,

[0196] are prepared, for example, analogously to the following scheme 1

[0197] In all formulae of scheme 1,

[0198] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0199] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms.

[0200] In the compounds of the formula IIa, Z is NH or NA′, where A′ isas defined in Claim 1.

[0201] In the compounds of the formula IIb,

[0202] A and A′ are each, independently of one another, H or alkylhaving 1, 2, 3 or 4 carbon atoms, and

[0203] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0204] and where n, R²⁰, R ⁵, R⁶ and R⁹ are as defined in Claim 1.

[0205] In the compounds of the formula IIc, Z is NH or NA′, where A′ isas defined in Claim 1.

[0206] Compounds of the formula II

[0207] in which

[0208] Z is O,

[0209] L is Cl,

[0210] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0211] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0212] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms,

[0213] and n, R²⁰ , R⁵, R⁶ and R⁹ are as defined in Claim 1, areprepared, for example, analogously to the following scheme 2

[0214] In all formulae of scheme 2,

[0215] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0216] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms.

[0217] In the compounds of the formula IId,

[0218] A and A′ are each, independently of one another, H or alkylhaving 1, 2, 3 or 4 carbon atoms, and

[0219] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0220] and where n, R²⁰, R⁵, R⁶ and R⁹ are as defined in Claim 1.

[0221] In the compounds of the formula IIe, Z is O (oxygen).

[0222] Compounds of the formula II

[0223] in which

[0224] Z is O,

[0225] L is Cl,

[0226] Y is (CH₂)_(q)—R⁷,

[0227] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0228] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms,

[0229] q and R⁷ are as defined in Claim 1,

[0230] and where R⁷ contains at least one N atom,

[0231] are prepared, for example, analogously to the following scheme 3

[0232] In all formulae of scheme 3,

[0233] R³ and R⁴ are each, independently of one another, H, A or Hal,

[0234] R³ and R⁴ together are alternatively alkylene or alkylidenehaving 3-5 carbon atoms.

[0235] In the compounds of the formula IIf,

[0236] A and A′ are each, independently of one another, H or alkylhaving 1, 2, 3 or 4 carbon atoms, and

[0237] Hal is Cl or Br.

[0238] In the compounds of the formula IIg,

[0239] Z is O,

[0240] q is 0,1,2,3 or 4,

[0241] Hal is Br or Cl.

[0242] In the compounds of the formula IIh, R⁷ is as defined in Claim 1,where the heterocyclic radical contains at least one substitutablenitrogen.

[0243] Compounds of the formula II

[0244] in which

[0245] Z is NH,

[0246] L is Cl,

[0247] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0248] R³ and R⁴ together are

[0249] n, R²⁰, R⁵, R⁶ and R⁹ are as defined in Claim 1, are prepared,for example, analogously to the following scheme 4

[0250] In all formulae of scheme 4,

[0251]1 R³ and R⁴ together are

[0252] where R¹⁰, R¹¹, R¹² and R¹³ are as defined in Claim 1.

[0253] The compounds of the formula IIi are prepared, for example,analogously to I. T. Fordes, C. N. Johnson, M. Thompson, J. Chem. Soc.Perkin Trans. 1, 2, 275-282 (1992).

[0254] In the compounds of the formula IIi, A′ is alkyl having 1, 2, 3or 4 carbon atoms.

[0255] In the compounds of the formula IIj, A′ is alkyl having 1, 2, 3or 4 carbon atoms.

[0256] In the compounds of the formula IIk, Y is R⁵, R⁶ or R⁹, each ofwhich is unsubstituted or monosubstituted by (CH₂)_(n)R²⁰, where n, R²⁰,R⁵, R⁶ and R9 are as defined in Claim 1.

[0257] In the compounds of the formula Iim, A′ is alkyl having 1, 2, 3or 4 carbon atoms, and Y is R⁵, R⁶ or R⁹, each of which is unsubstitutedor monosubstituted by (CH₂)_(n)R²⁰, where n, R²⁰, R⁵, R⁶ and R⁹ are asdefined in Claim 1.

[0258] In the compounds of the formula IIn, Y is R⁵, R⁶ or R⁹, each ofwhich is unsubstituted or monosubstituted by (CH₂)_(n)R²⁰, where n, R²⁰,R⁵, R ⁶ and R⁹ are as defined in Claim 1.

[0259] Compounds of the formula II

[0260] in which

[0261] Z is NA′,

[0262] L is Cl,

[0263] Y is R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰,

[0264] R³ and R⁴ together are

[0265] A′, n, R²⁰, R⁵, R⁶ and R⁹ are as defined in Claim 1, areprepared, for example, analogously to the following scheme 5

[0266] In all formulae of scheme 5,

[0267] R³ and R⁴ together are

[0268] where R¹⁰, R¹¹, R¹² and R¹³ are as defined in Claim 1.

[0269] In the compounds of the formulae IIs and Iiu, A′ is as defined inClaim 1. In compound IIt, Y is R⁵, R⁶ or R⁹, each of which isunsubstituted or monosubstituted by (CH₂)_(n)R²⁰, where n, R²⁰, R⁵, R⁶and R⁹ are as defined in Claim 1.

[0270] In detail, the reaction of the compounds of the formula II withthe compounds of the formula III is carried out in the presence orabsence of an inert solvent at temperatures between about −20 and about150°, preferably between 20 and 100°.

[0271] The addition of an acid-binding agent, for example an alkali oralkaline earth metal hydroxide, carbonate or bicarbonate or another saltof a weak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium or calcium, or the addition of an organic base, suchas triethylamine, dimethylamine, pyridine or quinoline or of an excessof the amine component, may be favourable.

[0272] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, iso-propanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone or dimethyl-formamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters,such as ethyl acetate, or mixtures of the said solvents.

[0273] It is furthermore possible to convert a radical X in a compoundof the formula I into another radical X, for example by hydrolysing anester or a cyano group to give a COOH group.

[0274] Ester groups can be saponified, for example, using NaOH or KOH inwater, water/THF or water/dioxane at temperatures between 0 and 100°.Carboxylic acids can be converted into the corresponding carboxylic acidchlorides, for example using thionyl chloride, and these can beconverted into carboxamides. Elimination of water therefrom in a knownmanner gives carbonitriles.

[0275] An acid of the formula I can be converted into the associatedacid-addition salt using a base, for example by reaction of equivalentamounts of the acid and the base in an inert solvent, such as ethanol,followed by evaporation. Suitable bases for this reaction are, inparticular, those which give physiologically acceptable salts.

[0276] Thus, the acid of the formula I can be converted into thecorresponding metal salt, in particular alkali metal or alkaline earthmetal salt, or into the corresponding ammonium salt using a base (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Also suitable for this reaction are, inparticular, organic bases which give physiologically acceptable salts,such as, for example, ethanolamine.

[0277] On the other hand, a base of the formula I can be converted intothe associated acid-addition salt using an acid, for example by reactionof equivalent amounts of the base and the acid in an inert solvent, suchas ethanol, followed by evaporation. Suitable acids for this reactionare, in particular, those which give physiologically acceptable acids.Thus, it is possible to use inorganic acids, for example sulfuric acid,nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromicacid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, orlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

[0278] Compounds of the formula I according to the invention may bechiral owing to their molecular structure and may accordingly occur invarious enantiomeric forms. They may therefore be in racemic or inoptically active form.

[0279] Since the pharmaceutical efficacy of the racemates or thestereoisomers of the compounds according to the invention may differ, itmay be desirable to use the enantiomers. In these cases, the endproduct, or, however, even the intermediates may be resolved to giveenantiomeric compounds by chemical or physical measures known to theperson skilled in the art or employed as such in the synthesis.

[0280] In the case of racemic amines, diastereomers are formed from themixture by reaction with an optically active resolving agent. Examplesof suitable resolving agents are optically active acids, such as the Rand S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, mandelic acid, malic acid, lactic acid, suitably N-protected aminoacids (for example N-benzoylproline or N-benzenesulfonylproline) or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

[0281] The invention furthermore relates to the use of the compounds ofthe formula I and/or physiologically acceptable salts thereof for thepreparation of a medicament (pharmaceutical preparation), in particularby non-chemical methods. They can be converted into a suitable dosageform here together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and optionally in combination with one or morefurther active ingredients.

[0282] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and physiologically acceptablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and, if desired, excipients and adjuvants.

[0283] The invention furthermore relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

[0284] These preparations can be used as medicaments in human orveterinary medicine. Suitable excipients are organic or inorganicsubstances which are suitable for enteral (for example oral), parenteralor topical administration and do no react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose or starch, magnesium stearates, talc or Vaseline. Suitablefor oral administration are, in particular, tablets, pills, coatedtablets, capsules, powders, granules, syrups, juices or drops, suitablefor rectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders or also as a nasal spray.The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, for the preparation of injectionpreparations. The preparations indicated may be sterilised and/orcomprise adjuvants, such as lubricants, preservatives, stabilisersand/or wetting agents, emulsifiers, salts for modifying the osmoticpressure, buffer substances, colorants and flavours and/or a pluralityof further active ingredients, for example one or more vitamins.

[0285] The compounds of the formula I and physiologically acceptablesalts thereof can be employed for combating diseases in which anincrease in the cGMP (cycloguanosine monophosphate) level results ininflammation inhibition or prevention and muscle relaxation. Thecompounds according to the invention are used in particular in thetreatment of diseases of the cardiovascular system and for the treatmentand/or therapy of potency disorders in humans.

[0286] The invention relates to the use of the compounds of the formulaI and physiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for the treatment of angina, high bloodpressure, pulmonary hypertension, congestive heart failure, cardiacinfarction, chronic obstructive pulmonary disease (COPD), cor pulmonale,dextrocardiac insufficiency, atherosclerosis, conditions of reducedpatency of the heart vessels, peripheral vascular diseases, strokes,bronchitis, allergic asthma, chronic asthma, allergic rhinitis,glaucoma, irritable bowel syndrome, tumours, renal insufficiency, livercirrhosis, for the treatment of female sexual disorders, inflammation,osteoporosis, for the treatment of malign hypertonia, phaeochromacytoma,peripheral vascular (occlusion) diseases, vascular diseases,thrombocytopenia, ulcus pepticum, peristaltic motion disorders,percutaneous transluminal coronary angioplasty, carotid angioplasty,postoperative stenosis of the coronary bypass, premonitory pains andbenign prostate hyperplasia.

[0287] In general, the substances are preferably administered in dosesof between about 1 and 500 mg, in particular between 5 and 100 mg perdosage unit. The daily dose is preferably between about 0.02 and 10mg/kg of body weight. However, the specific dose for each patientdepends on a wide variety of factors, for example on the efficacy of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and method of administration, onthe excretion rate, medicament combination and severity of theparticular disease to which the therapy applies. Oral administration ispreferred.

[0288] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and/or physiologically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activeingredient.

[0289] The invention also relates to a set (kit) consisting of separatepacks of

[0290] (a) an effective amount of a compound of the formula I and/orphysiologically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios,

[0291] and

[0292] (b) an effective amount of a further medicament activeingredient.

[0293] The set comprises suitable containers, such as boxes, individualbottles, cartons, bags or ampoules. The set may comprise, for example,separate ampoules each containing an effective amount of a compound ofthe formula I and/or physiologically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

[0294] The invention furthermore relates to the use of compounds of theformula I and/or physiologically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of diseases of thecardiovascular system, for the treatment and/or therapy of potencydisorders, such as, for example, erectile dysfunction, for the treatmentof angina, high blood pressure, pulmonary hypertension, congestive heartfailure, cardiac infarction, chronic obstructive pulmonary disease(COPD), cor pulmonale, dextrocardiac insufficiency, atherosclerosis,conditions of reduced patency of the heart vessels, peripheral vasculardiseases, strokes, bronchitis, allergic asthma, chronic asthma, allergicrhinitis, glaucoma, irritable bowel syndrome, tumours, renalinsufficiency, liver cirrhosis, for the treatment of female sexualdisorders, inflammation, osteoporosis, furthermore for the treatment ofmalign hypertonia, phaeochromacytoma (catecholamine-producing tumour ofthe pituitary cortex), in peripheral vascular (occlusion) diseases,vascular diseases, thrombocytopenia, ulcus pepticum (benign intestinalulcer), peristaltic motion disorders, percutaneous transluminal coronaryangioplasty, carotid angioplasty, postoperative stenosis of the coronarybypass, premonitory pains and benign prostate hyperplasia, incombination with at least one further medicament active ingredient.

[0295] The compounds of the formula I according to the invention can beused together with other active ingredients, such as, for example, withvasodilators, α-adrenergic inhibitors, such as, for example,phentolamin, prazocin or yohimbin, mixed α,β-inhibitors, such as, forexample, carvedilol, prostaglandin El and prostacyclin, ACE (angiotensinconverting enzyme) inhibitors, NEP (neutral endopeptidase) inhibitors,centrally acting dopaminergic active ingredients, such as, for example,apomorphine, vaso-active intestinal peptides, calcium channel blockersand compounds such as thiazides.

[0296] The invention therefore relates to pharmaceutical formulationscomprising a prostaglandin or prostaglandin derivative and at least onecompound of the formula I.

[0297] Preference is given to prostaglandins or prostaglandinderivatives selected from the group consisting of PGE₀, PGA₁, PGB₁,PGF_(1□), PGA₂, PGB₂, 19-hydroxy-PGA₁, 19-hydroxy-PGB₁, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃, PGF_(3□), alprostadil (PGE₁), dinoprost (PGF₂),dinoprostone (PGE₂), epoprostenol sodium (PGI₂; prostacyclin sodium),gemeprost, iloprost, latanoprost, misoprostol, sulprostone, carboprostthromethamin, dinoprost thromethamin, lipoprost, metenoprost andtiaprost.

[0298] Particular preference is given to prostaglandins or prostaglandinderivatives selected from the group consisting of alprostadil (PGE₁),dinoprost (PGF₂), dinoprostone (PGE₂), epoprostenol sodium (PGI₂;prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol,sulprostone, carboprost thromethamin, dinoprost thromethamin, lipoprost,metenoprost and tiaprost.

[0299] Particular preference is given to PGE₁ or prostacyclin,especially preferably prostacyclin.

[0300] The invention preferably relates to pharmaceutical formulationscomprising a calcium antagonist and at least one compound of the formulaI.

[0301] Preference is given to calcium antagonists selected from thegroup consisting of selective and non-selective calcium antagonists.

[0302] Preference is given to selective calcium antagonists selectedfrom the group consisting of dihydropyridine derivatives,phenylalkylamine derivatives, benzothiazepine derivatives and otherselective calcium antagonists.

[0303] Dihydropyridine derivatives are preferably selected from thegroup consisting of amlodipine, felodipine, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine,nilvadipine, manidipine, barnidipine and lercanidipine.

[0304] The phenylalkylamine derivatives are preferably selected from thegroup consisting of verapamil and gallopamil.

[0305] The benzothiazepine derivatives are preferably diltiazem.

[0306] The other selective calcium antagonists are preferablymibefradil.

[0307] The non-selective calcium antagonists are preferably selectedfrom the group consisting of fendiline, bepridil, lidoflazine andperhexiline.

[0308] The invention furthermore relates to pharmaceutical formulationscomprising an antithrombotic and at least one compound of the formula I.

[0309] The term antithrombotics also includes so-called anticoagulantsand blood platelet aggregation inhibitors (thrombocyte aggregationinhibitors).

[0310] Preferred antithrombotics are vitamin K antagonists, heparincompounds, thrombocyte aggregation inhibitors, enzymes, factor Xainhibitors, factor VIIa inhibitors and other antithrombotic agents.

[0311] Preferred vitamin K antagonists are selected from the groupconsisting of dicoumarol, phenindione, warfarin, phenprocoumon,acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione andtioclomarol.

[0312] Preferred heparin compounds are selected from the groupconsisting of heparin, antithrombin III, dalteparin, enoxaparin,nadroparin, parnaparin, reviparin, danaparoid, tinzaparin andsulodexide.

[0313] Preferred thrombocyte aggregation inhibitors are selected fromthe group consisting of ditazole, cloricromen, picotamide, clopidogrel,ticlopidine, acetylsalicylic acid, dipyridamole, calcium carbassalate,epoprostenol, indobufen, iloprost, abciximab, tirofiban, aloxiprin andintrifiban.

[0314] Preferred enzymes are selected from the group consisting ofstreptokinase, alteplase, anistreplase, urokinase, fibrinolysin,brinase, reteplase and saruplase.

[0315] Preferred antithrombotics are furthermore the blood plateletglycoprotein receptor (IIb/IIIa) antagonists which inhibit bloodplatelet aggregation.

[0316] Preferred compounds are described, for example, in EP 0 623615 B1on page 2 or in EP 0 741 133 A2, page 2, line 2, to page 4, line 56.

[0317] Preferred factor Xa and VIIa inhibitors are, for example, thecompounds of the formula I described in WO 99/16751, WO 99/31092, WO99/57096, WO 00/12479, WO 00/20416, WO 00/40583 and WO 00/51989.

[0318] Other preferred factor Xa inhibitors are, for example, thecompounds described in the following documents:

[0319] a) in WO 97/30971, page 4, line 5, to page 13, line 19;

[0320] b) in EP 0 921 116 A1, page 2, line 1, to line 51;

[0321] c) in EP 0 540 051 B1, page 2, line 41, to page 3, line 14;

[0322] d) in EP 0 798 295 A1, page 69, line 10, to page 71, page 53.

[0323] Other preferred compounds are selected from the group consistingof defibrotide, desirudin and lepirudin.

[0324] The invention also relates to pharmaceutical formulationscomprising an endothelin receptor antagonist and at least one compoundof the formula I.

[0325] Preferred endothelin receptor antagonists are bosentan,tezosentan and sitaxentan (TBC-1 1251; J.Med.Chem., 40, No.11, 1690-97,1997).

[0326] Preferred endothelin receptor antagonists are thus furthermore

[0327] a) BMS-193884 (EP 558258),

[0328] b) BMS-207940 (Pharmaprojects (13. 06. 97)),

[0329] c) BQ-123 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),

[0330] d) SB-209670 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),

[0331] e) SB-217242 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),

[0332] f) SB-209598 (Trends in Pharmacol. Sci., 17, 177-81,1996),

[0333] g) TAK-044 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),

[0334] h) Bosentan (Trends in Pharmacol. Sci., 18, 408-12, 1997),

[0335] i) PD-156707 (J. Med. Chem., 40, No. 7, 1063-74, 1997),

[0336] j) L-749329 (Bioorg. Med. Chem. Lett., 7, No. 3, 275-280,1997),

[0337] k) L-754142 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),

[0338] I) ABT-627 (J. Med. Chem., 40, No. 20, 3217-27,1997),

[0339] m) A-127772 (J. Med. Chem., 39, No. 5, 1039-1048, 1996),

[0340] n) A-206377 (213^(th) American Chemical Society National Meeting,San Francisco, Calif., USA, 13-17 Apr. 1997, Poster, MEDI 193),

[0341] o) A-182086 (J. Med. Chem., 40, No. 20, 3217-27, 1997),

[0342] p) EMD-93246 (211^(th) American Chemical Society NationalMeeting, New Orleans, USA, 1996, Poster, MEDI 143),

[0343] q) EMD-122801 (Bioorg. Med. Chem. Lett., 8, No. 1, 17-22, 1998),

[0344] r) ZD-1611 (Trends in Pharmacol. Sci., 18,408-12, 1997),

[0345] s) AC-610612 (R&D Focus Drug News (18.05.98)),

[0346] t) T-0201 (70^(th) Annual Meeting of the Japanese PharmacologicalSociety, Chiba, Japan, 22-15 Mar. 1997, Lecture, O-133),

[0347] u) J-104132 (R&D Focus Drug News (15.12.97)),

[0348] Particularly preferred endothelin receptor antagonists are, forexample, the compounds of the formula I described in EP 0733626, EP0733626, EP 0755934, EP 0757039, EP 0796250, WO 97/19077, WO 97/30982,WO 97/30996, DE 19609597, DE 19612101, WO 98/27091, WO 98/27077, WO98/41515, WO 98/41521, WO 98/42702, WO 98/42709 or WO 99/05132.

[0349] The invention furthermore relates to pharmaceutical formulationscomprising a vasodilator, such as, for example, a nitrate, and at leastone compound of the formula I.

[0350] The invention preferably relates to pharmaceutical formulationscomprising at least one compound of the formula I and a vasodilator,such as, for example, (a) an organic nitrate, for examplenitroglycerine, isosorbide mononitrate, isosorbide dinitrate,pentaerythrityl tetra-, tri-, di-, tri- or mono-nitrate, propatylnitrate, trol nitrate, nicroandil, mannitol hexanitrate, inositolhexanitrate, N-[3-nitratopivaloyl]-L-cysteine ethyl ester, (b) anorganic nitrite, for example isoamyl nitrite, (c) a thionitrite, (d) athionitrate, (e) an S-nitrosothiol, such as, for example,S-nitroso-N-acetyl-D,L-penicillamine, (f) nitrosoproteins, (g)substituted furoxanes, such as, for example, 1,2,5-oxadiazole 2-oxidesor furazane N-oxides, (h) substituted sydnonimines, such as, forexample, molsidomine or mesocarb, (i) complex nitrosyl compounds, suchas, for example, iron nitrosyl compounds, preferably sodiumnitroprusside, or (j) nitrogen oxide NO, which is inhaled.

[0351] Preferred vasodilators are nitrates selected from the groupconsisting of pentaerythrityl tetra-, tri-, di- and mononitrate,isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate.

[0352] Particular preference is given to nitrates selected from thegroup consisting of pentaerythrityl tetranitrate, isosorbidemononitrate, isosorbide dinitrate, glycerol trinitrate, veryparticularly preferably pentaerythrityl tetranitrate.

[0353] The invention furthermore relates to the use of a pharmaceuticalformulation comprising at least one compound of the formula I and atleast one antithrombotic for the preparation of a medicament for thetreatment of pulmonary hypertension, congestive heart failure (CHF),chronic obstructive pulmonary disease (COPD), cor pulmonale and/ordextrocardiac insufficiency.

[0354] α-adrenergic inhibitors inhibit the vasoconstriction in thecorpus cavernosum. Since PDE V inhibitors increase vasodilation of thesame tissue of the smooth muscles, potency disorders (erectiledysfunction) can preferably also be treated using pharmaceuticalformulations comprising at least one compound of the formula I and atleast one a-adrenergic inhibitor, such as, for example, phentolamin orprazocin, or at least one centrally acting dopaminergic activeingredient, such as, for example, apomorphine.

[0355] The invention therefore furthermore relates to the use of apharmaceutical formulation comprising at least one compound of theformula I and at least one α-adrenergic inhibitor, such as, for example,phentolamin or prazocin, or at least one centrally acting dopaminergicactive ingredient, such as, for example, apomorphine, for thepreparation of a medicament for the treatment of potency disorders.

[0356] The invention furthermore relates to the use of a pharmaceuticalformulation comprising at least one compound of the formula I and acalcium antagonist for the preparation of a medicament for the treatmentof pulmonary hypertension, congestive heart failure (CHF), chronicobstructive pulmonary disease (COPD), cor pulmonale and/or dextrocardiacinsufficiency.

[0357] The invention furthermore relates to the use of a pharmaceuticalformulation comprising at least one compound of the formula I and atleast one nitrate for the preparation of a medicament for the treatmentof pulmonary hypertension, congestive heart failure (CHF), chronicobstructive pulmonary disease (COPD), cor pulmonale and/or dextrocardiacinsufficiency.

[0358] The invention furthermore relates to the use of a pharmaceuticalformulation comprising at least one compound of the formula I and atleast one endothelin receptor antagonist for the preparation of amedicament for the treatment of pulmonary hypertension, congestive heartfailure (CHF), chronic obstructive pulmonary disease (COPD), corpulmonale and/or dextrocardiac insufficiency.

[0359] The invention furthermore relates to the use of a pharmaceuticalformulation comprising at least one compound of the formula I and atleast one prostaglandin or a prostaglandin derivative for thepreparation of a medicament for the treatment of pulmonary hypertension,congestive heart failure (CHF), chronic obstructive pulmonary disease(COPD), cor pulmonale and/or dextrocardiac insufficiency.

[0360] Above and below, all temperatures are given in ° C. In thefollowing examples, “conventional work-up” means that water is added ifnecessary, the pH is adjusted, if necessary, to between 2 and 10,depending on the constitution of the end product, the mixture isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation.

[0361] Mass spectrometry (MS): El (electron impact ionisation)M^(+FAB (fast atom bombardment) (M+H)) ⁺

EXAMPLE 1 Preparation of4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid

[0362] 1.1 A solution of 56.6 g of 2-hydroxycyclohexanone, 60.6 g ofphenethylamine and a catalytic amount of p-toluenesulfonic acid in 400ml of cyclohexanone is refluxed for 10 hours on a water separator. Thesolution is cooled to 50°, 10 ml of piperidine and 30 ml ofmalononitrile, dissolved in hot cyclohexanone, are then added, and themixture is refluxed for a few hours more.

[0363] Removal of the solvent and conventional work-up give 45 g of2-amino-1-(1-phenylethyl)-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile(“AA”), m.p. 129°,

[0364] 1.2 1 ml of POCl₃ is added with ice cooling to 1.8 g of methyl4-N,N-dimethylaminocarbonylbenzoate, and the mixture is stirred forabout a further 30 minutes. 2 g of “AA” are added, and the mixture isstirred at 80° for 3 hours, then subjected to conventional work-up,giving 1.6 g of methyl4-[4-chloro-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoate(“AB”),

[0365] 1.3 3-chloro-4-methoxybenzylamine is added to a solution of 1.6 gof “AB” in 30 ml of 1-methyl-2-pyrrolidone, and the mixture is stirredat 100° for 4 hours. Conventional work-up gives 1.4 g of methyl4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoate(“AC”).

[0366] 1.4 20 ml of NaOH are added to 0.5 g of “AC” in 20 ml of ethyleneglycol monoethyl ether, and the mixture is heated on a steam bath for 3hours. The ether is removed, and the residue is diluted with water andwashed with ethyl acetate. The ethyl acetate is discarded. The mixtureis acidified using glacial acetic acid, and the crystals which depositare separated off. The residue is dissolved in methanol, and methanolicKOH is added. The methanol is removed under reduced pressure. Water isadded to the residue, and the crystals which deposit are filtered offwith suction, giving 0.11 g of4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid, potassium salt, m.p. 179°.

[0367] Affinity to PDE V: IC₅₀ [mol/l]3.0E-07

[0368] Analogous reaction of

[0369] methyl4-[4-chloro-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]-benzoate

[0370] with

[0371] benzylamine,

[0372] 3,4-dimethoxybenzylamine,

[0373] 3,4-dichlorobenzylamine,

[0374] 3,4-methylenedioxybenzylamine

[0375] followed by ester hydrolysis gives

[0376]4-[4-benzylamino-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid;

[0377]4-[4-(3,4-dimethoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetra-hydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid;

[0378]4-[4-(3,4-dichlorobenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid;

[0379]4-[4-(3,4-methylenedioxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetra-hydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid.

[0380] Analogous reaction of

[0381] methyl4-[4-chloro-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]-butyrate

[0382] with

[0383] 3-chloro-4-methoxybenzylamine,

[0384] benzylamine,

[0385] 3,4-dimethoxybenzylamine,

[0386] 3,4-dichlorobenzylamine,

[0387] 3,4-methylenedioxybenzylamine

[0388] followed by ester hydrolysis gives

[0389]4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetra-hydro-5H-1,3,9-triazafluoren-2-yl]butyricacid, ethanolamine salt;

[0390]4-[4-benzylamino-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid;

[0391]4-[4-(3,4-dimethoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetra-hydro-5H-1,3,9-triazafluoren-2-yl]butyricacid;

[0392]4-[4-(3,4-dichlorobenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid;

[0393]4-[4-(3,4-methylenedioxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetra-hydro-5H-1,3,9-triazafluoren-2-yl]butyricacid.

EXAMPLE 2 Preparation of4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid

[0394]

[0395] 2.1 4.8 ml of triethylamine are added dropwise to a solution of11.0 g of 2-hydroxycyclohexanone and 9.6 g of malononitrile in 25 ml ofmethanol, and the mixture is stirred at room temperature for a further 4hours. The crystals which deposit are separated off and washed withmethanol, giving 12.8 g of2-amino-4,5,6,7-tetrahydrobenzofuran-3-carbonitrile (“BA”), m.p. 179°.

[0396] 2.2 30 ml of a 40% dimethylamine solution in 200 ml of THF areinitially introduced. 20 g of methyl 4-chlorocarbonylbenzoate aredissolved in 300 ml of THF and added dropwise, and the mixture isstirred at room temperature for a further 2 hours. The solvent isremoved, and the mixture is subjected to conventional work-up, giving19.2 g of methyl 4-(N,N-dimethylaminocarbonyl)benzoate (“BB”), m.p.107°.

[0397]2.3 3.3 ml of POCl₃ are added to 5.0 g of “BB” with ice cooling,and the mixture is stirred for about a further 30 minutes. 5.9 g of “BA”are then added, and the mixture is stirred at 80° for 3 hours.

[0398] Conventional work-up gives 5.2 g of methyl4-(4-chloro-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-yl)benzoate(“BC”), amorphous.

[0399] 2.4 2.4 g of 3,4-methylenedioxybenzylamine are added to asolution of 2.5 g of “BC” in 30 ml of 1-methyl-2-pyrrolidone, and themixture is stirred at 100° for 4 hours. The mixture is subjected toconventional work-up, giving 2.2 g of methyl4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetra-hydrobenzo[4,5]furo[2,3-pyrimidin-2-yl]benzoate(“BD”).

[0400] 2.5 10 ml of NaOH are added to 1.0 g of “BD” in 10 ml of ethyleneglycol monoethyl ether, and the mixture is heated on a steam bath for 3hours. The ether is removed, and the residue is diluted with water andwashed with ethyl acetate. The ethyl acetate is discarded. The mixtureis acidified using glacial acetic acid, and the crystals which depositare separated off. The residue is dissolved in isopropanol, andethanolamine is added. Salt is etherified out, giving 0.5 g of4-[4-(3,4-methylenedioxy-benzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid, ethanolamine salt, m.p. 205°.

[0401] Analogous reaction of

[0402] methyl4-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl)benzoate

[0403] with

[0404] 3-chloro-4-methoxybenzylamine,

[0405] benzylamine,

[0406] 3,4-dimethoxybenzylamine,

[0407] 3,4-dichlorobenzylamine,

[0408] C-pyridin-3-ylmethylamine

[0409] followed by ester hydrolysis gives

[0410]4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-furo[2,3-d]pyrimidin-2-yl]benzoicacid, ethanolamine salt, m.p. 205°;

[0411]4-(4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl)benzoicacid, ethanolamiine salt;

[0412] 4-[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo-[2,3-d]pyrimidin-2-yl]benzoic acid, ethanolamine salt;

[0413]4-[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo-[2,3-d]pyrimidin-2-yl]benzoicacid, ethanolamine salt;

[0414]4-{4-[(pyridin-3-ylmethyl)amino]-5,6,7,8-tetrahydrobenzo[4,5]furo-[2,3-d]pyrimidin-2-ylbenzoicacid, ethanolamine salt, m.p.>250°.

EXAMPLE 3 Preparation of Preparation of4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid

[0415] 3.1 3.3 ml of POCl₃ are added with ice cooling to 5.5 g of methyl4-(N,N-dimethylcarbamoyl)butyrate, and the mixture is stirred for abouta further 30 minutes. 5.9 g of “BA” are then added, and the mixture isstirred at 80° for 3 hours.

[0416] Conventional work-up gives 5.2 g of methyl4-(4-chloro-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-yl)butyrate(“CA”), amorphous.

[0417] 3.2 2.3 g of 3-chloro-4-methoxybenzylamine are added to asolution of 2.0 g of “CA” in 20 ml of 1-methyl-2-pyrrolidone, and themixture is stirred at 80° for 3 hours. The mixture is subjected toconventional work-up, giving 2.2 g of methyl4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-yl]butyrate(“CB”).

[0418] 3.3 10 ml of 2N NaOH are added to 0.8 g of “CB” in 10 ml ofmethanol, and the mixture is stirred at 50° for a further 2 hours. Thealcohol is removed, and the residue is diluted with water and washedwith ethyl acetate. The ethyl acetate is discarded. The mixture isacidified using HCl and subjected to conventional work-up. The residueis dissolved in ethanol, and cyclohexylamine is added. The crystalswhich deposit are washed with ether, giving 0.25 g of4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]butyricacid, cyclohexylamine salt, m.p. 205°.

[0419] Analogous reaction of

[0420] methyl4-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl)butyratewith 3,4-methylenedioxybenzylamine followed by ester hydrolysis gives

[0421]4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-furo[2,3-d]pyrimidin-2-yl]butyricacid, cyclohexylamine salt.

EXAMPLE 4 Preparation of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperidine-4-carboxylicacid

[0422]

[0423] 4.1 6.7 ml of POCl₃ are added dropwise with stirring and coolingto 6.2 ml of 2-chlorodimethylacetamide, and the mixture is stirred atroom temperature for a further 10 minutes. 10.0 g of “BA” are added, andthe mixture is stirred at 80° for a further 30 minutes. Conventionalwork-up gives 8.3 g of4-chloro-2-chloromethyl-5,6,7,8-tetrahydrobenzo[4,5]furo-[2,3-d]pyrimidine(“DA”) as an oil.

[0424] 4.2 10 ml of ethyl piperidine-4-carboxylate are added to asolution of 8.3 g of “DA” in 100 ml of THF, and the mixture is stirredat room temperature for a further 16 hours.

[0425] Water is added, and the mixture is extracted with methyltert-butyl ether (MTB). The MTB extract (“X”) is extracted with diluteHCl.

[0426] The HCl extract is rendered alkaline using dilute NaOH, extractedwith MTB and subjected to conventional work-up, giving 2.9 g of ethyl1-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl)-piperidine-4-carboxylate(“DB”).

[0427] “X” contains the by-product ethyl1-(2-chloromethyl-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate.

[0428] 4.3 3.0 g of 3-chloro4-methoxybenzylamine are added to a solutionof 2.9 g of “DB” in 50 ml of 1-methyl-2-pyrrolidone, and the mixture isstirred over a steam bath for 1 hour. The mixture is subjected toconventional work-up, giving 2.9 g of ethyl1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperidine-4-carboxylate(“DC”), m.p. 152°.

[0429] 4.4 3 ml of NaOH (about 30%) are added to 2.8 g of “DC” in 30 mlof ethylene glycol monoethyl ether, and the mixture is stirred at 60°for a further 1 hour. The ether is removed, and the mixture is acidifiedto pH 4 using acetic acid. The crystals which deposit are washed withice-water, giving 1.5 g of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperidine-4-carboxylicacid, m.p. 233-235°.

EXAMPLE 5 Preparation of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro-benzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]-4-methylsulfonylpiperazine

[0430] 5.1 2.85 g of ethyl piperazine-N-carboxylate are added dropwiseto a solution of 4.7 g of “DA” and 1.8 g of triethylamine buffersubstance f in 50 g of dichloromethane, and the mixture is stirred for afurther 16 hours. The mixture is subjected to conventional work-up,giving 3.0 g of1-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl)-4-ethoxycarbonylpiperazine(“EA”) as an oil.

[0431] 5.2 3.49 g of 3-chloro-4-methoxybenzylamine are added to asolution of 3.4 g of “EA” in 80 ml of 1,4-dioxane, and the mixture isstirred at 115° for 16 hours. The crystals which deposit and the solventare separated off. 10 ml of 1-methyl-2-pyrrolidone are added to theresidue, and the mixture is stirred at 115° for 1.5 hours. The mixtureis subjected to conventional work-up, giving 3.25 g of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]-4-ethoxycarbonyl-piperazine(“EB”).

[0432] 5.3 3.5 ml of 32% NaOH are added to a solution of 3.25 g of “EB”in 20 ml of ethylene glycol monoethyl ether, and the mixture is stirredat 110° for a further 5 hours. Conventional work-up gives 1.99 g of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperazine(“EC”) as an oil.

[0433] 5.4 520 mg of methanesulfonyl chloride are added dropwise to asolution of 2.0 g of “EC” and 360 mg of pyridine in 50 ml ofdichloromethane, and the mixture is stirred at room temperature for afurther 3 hours. Conventional work-up gives 1.0 g of1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]-4-methyl-sulfonylpiperazine,dihydrochloride.

EXAMPLE 6 Preparation of4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triaza-fluoren-2-yl]butyricacid

[0434]

[0435] 6.1 Ammonia is passed into 350 ml of cold THF for 30 minutes. 30g of methyl 4-chlorocarbonylbutyrate are then added dropwise, withammonia continuing to be passed in at the same time. The crystals whichdeposit are separated off, and the residue is boiled a number of timeswith ethyl acetate. The combined filtrates are distilled off, and theresidue is recrystallised from ethyl acetate, giving 23.4 g of methyl4-aminocarbonylbutyrate (“FA”), m.p. 80°.

[0436] 6.2 15 ml of oxalyl chloride are added dropwise at from −2 to 0°to a solution of 15 ml of DMF in 300 ml of acetonitrile, and the mixtureis stirred for a further 30 minutes. 23.25 g of “FA” are added dropwiseat a maximum of 0°, and, after the mixture has been stirred for 15minutes, 29 ml of pyridine are added dropwise. Ether is added, and themixture is subjected to conventional work-up, giving 20 g of methyl4-cyanobutyrate (“FB”) as an oil.

[0437] 6.3 A solution of 180 ml of methyl cyanoacetate in 300 ml of DMFis added dropwise at 0-50° with stirring and under a nitrogen atmosphereto a solution of 88 g of NaH suspension in 2 litres of DMF. The mixtureis stirred for a further 30 minutes without cooling. A solution of 106ml of o-fluoronitrobenzene in 100 ml of DMF is subsequently addeddropwise, and the mixture is stirred at room temperature for a further14 hours. The mixture is acidified using 10% HCl and subjected toconventional work-up, giving 165 g of methyl cyano(2-nitrophenyl)acetate(“FC”), m.p. 58-60°.

[0438] 6.4 A solution of 74 g of “FC” in 180 ml of acetic acid and 550ml of toluene is heated to 80°. 130 g of zinc powder are added inportions with stirring and while noting the temperature (80-85°), andthe mixture is stirred at room temperature for a further 14 hours.Conventional work-up gives 30 g of 2-amino-3-methoxycarbonylindole(“FD”), m.p. 136°.

[0439] 6.5 HCl is passed into a solution of 4.0 g of “FD” and 2.8 g of“FB” in 60 ml of 1,4-dioxane for 2 hours with stirring and at a maximumof 30°. The solution is left to stand for 48 hours. Conventional work-upgives 1.4 g of methyl2-[(4-methoxycarbonylbutyrimidoyl)amino]-1H-indole-3-carboxylate (“FE”),m.p. 95°,

[0440] 6.6 1.4 g of “FE” are added to 50 ml of acetic acid, and themixture is stirred on a steam bath for 1 hour and subjected toconventional work-up, giving 1.0 g of methyl4-(4-oxo-4,9-dihydro-3H-1,3,9-triazafluoren-2-yl)-butyrate (“FF”), m.p.258°,

[0441] 6.7 1.0 g of “FF” is refluxed for 3 hours with 40 ml of POCl₃.After the POCl₃ has been removed, the residue is treated 2× withdichloromethane, giving 1.0 g of methyl4-(4-chloro-9H-1,3,9-triazafluoren-2-yl)butyrate (“FG”), m.p. 258°,

[0442] 6.8 A solution of 1.0 g of “FG” and 1.0 g of3-chloro-4-methoxybenzyl-amine in 30 ml of 1-methyl-2-pyrrolidone isheated to 180°. After the solvent has been removed, the mixture isrecrystallised from n-butanol, giving 0.45 g of methyl4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triaza-fluoren-2-yl]butyrate(“FH”).

[0443] 6.9 A solution of 0.35 g of “FH” and 10 ml of 2N NaOH in 20 ml ofmethanol is heated on a steam bath for 1 hour. The methanol is removed,water is added, the mixture is acidified using HCl, and the product isseparated off, giving 300 mg of4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]butyricacid, m.p. 258°.

[0444] The acid is dissolved in methanol, and 2 drops of ethanolamineare added. Diethyl ether is added, and the crystals which deposit areisolated, giving 280 mg of4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]butyricacid, ethanolamine salt, m.p. 143°.

[0445] Analogous reaction of methyl 4-cyanobenzoate instead of “FB”gives the following compound

[0446]4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0447] The following compounds are obtained analogously

[0448]4-[4-(3,4-methylenedioxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-butyricacid,

[0449] 4-(4-benzylamino-9H-1,3,9-triazafluoren-2-yl)butyric acid,

[0450]4-[4-(3,4-dimethoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]butyricacid,

[0451]4-[4-(3,4-dichlorobenzylamino)-9H-1,3,9-triazafluoren-2-yl]butyric acid,

[0452]4-{4-[(pyridin-3-ylmethyl)amino]-9H-1,3,9-triazafluoren-2-yl}butyricacid,

[0453]4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-valericacid,

[0454]4-[4-(3,4-methylenedioxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-valericacid,

[0455] 4-(4-benzylamino-9H-1,3,9-triazafluoren-2-yl)butyric acid,

[0456]4-[4-(3,4-dimethoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]valericacid,

[0457]4-[4-(3,4-dichlorobenzylamino)-9H-1,3,9-triazafluoren-2-yl]valeric acid,

[0458]4-{4-[(pyridin-3-ylmethyl)amino]-9H-1,3,9-triazafluoren-2-yl}valericacid,

[0459]4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-cyclohexanecarboxylicacid,

[0460]4-[4-(3,4-methylenedioxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-cyclohexanecarboxylicacid,

[0461] 4-(4-benzylamino-9H-1,3,9-triazafluoren-2-yl)butyric acid,

[0462]4-[4-(3,4-dimethoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-cyclohexanecarboxylicacid,

[0463]4-[4-(3,4-dichlorobenzylamino)-9H-1,3,9-triazafluoren-2-yl]cyclohexanecarboxylicacid,

[0464]4-{4-[(pyridin-3-ylmethyl)amino]-9H-1,3,9-triazafluoren-2-yl}cyclohexanecarboxylicacid,

[0465]4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-benzoicacid,

[0466]4-[4-(3,4-methylenedioxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]-benzoicacid,

[0467] 4-(4-benzylamino-9H-1,3,9-triazafluoren-2-yl)benzoic acid,

[0468]4-[4-(3,4-dimethoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]benzoicacid,

[0469]4-[4-(3,4-dichlorobenzylamino)-9H-1,3,9-triazafluoren-2-yl]benzoic acid,

[0470]4-{4-[(pyridin-3-ylmethyl)amino]-9H-1,3,9-triazafluoren-2-yl}benzoicacid.

EXAMPLE 7 Preparation of4-[4-(3,4-methylenedioxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid

[0471] 7.1 448 g of NaH are introduced into 9 l of DMF, then 967 g ofcyanoacetamide are added in portions over the course of 1 hour at 2-8°with strong ice cooling and under a nitrogen atmosphere. The mixture isstirred for a further 30 minutes, 600 ml of 1-fluoro-2-nitrobenzene areadded, and the mixture is stirred for a further 2 hours. The mixture ispoured into 50 l of ice-water, acidified using 3 l of conc. HCl andsubjected to further conventional work-up, giving 956 g of2-cyano-2-(2-nitrophenyl)acetamide (“GA”), m.p. 172-174°.

[0472] 7.2 Analogously to Example 6.4, 956 g of “GA” give 352 g of2-amino-3-aminocarbonylindole (“GB”).

[0473] 7.3 13 g of NaH are suspended in 500 ml of DMF. A solution of52.6 g of “GB” in 200 ml of DMF is subsequently added dropwise withstirring at 0°. 26 ml of iodoethane in 100 ml of DMF are then addeddropwise at 0°, and the mixture is stirred for a further 1 hour. Themixture is subjected to conventional work-up, giving 67.9 g of2-amino-3-aminocarbonyl-1-ethylindole (“GC”).

[0474] 7.4 A solution of 10.0 g of “GC”, 8.0 g of methyl4-formylbenzoate and 9.4 g of sodium disulfite in 100 ml ofN,N-dimethylacetamide is stirred at 160° for 7 hours. Conventionalwork-up gives 4.8 g of methyl4-(9-ethyl-4-oxo-4,9-dihydro-3H-1,3,9-triazafluoren-2-yl)benzoate(“GD”).

[0475] 7.5 5 ml of DMF are added dropwise to a solution of 4.8 g of “GD”in 100 ml of thionyl chloride. The batch is left to stand for 60 hours.Conventional work-up gives 3.9 g of methyl4-(4-chloro-9-ethyl-9H-1,3,9-triaza-fluoren-2-yl)benzoate (“GE”).

[0476] 7.6 A solution of 2.4 g of “GE” and 2 ml of piperonylamine in 5ml of 1-methyl-2-pyrrolidone is stirred at a bath temperature of 110°for 2 hours. Conventional work-up gives 2.7 g of methyl4-[4-(3,4-methylenedioxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoate(“GF”).

[0477] 7.7 Treatment of 2.6 g of “GF” with 5 ml of NaOH (about 32%) in10 ml of ethylene glycol monoethyl ether gives 2.4 g of4-[4-(3,4-methylenedioxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0478] Analogous reaction of “GE” with 3-chloro-4-methoxybenzylaminefollowed by ester hydrolysis gives

[0479]4-[4-(3-chloro-4-methoxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

EXAMPLE 8 Preparation of4-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid

[0480] 8.1 A solution of 38 g of “GB”, 36.1 g of methyl 4-formylbenzoateand 41.8 g of sodium disulfite in 200 ml of N,N-dimethylacetamide isstirred at 140° for 3 hours. The product crystallises out, and washinggives 30 g of methyl4-(4-oxo-4,9-dihydro-3H-1,3,9-triazafluoren-2-yl)benzoate (“HA”),m.p.>250°.

[0481] 8.2 30 ml of DMF are added dropwise to a solution of 10 g of “HA”in 100 ml of thionyl chloride. The batch is left to stand for 16 hours.Conventional work-up gives 8.5 g of methyl4-(4-chloro-9H-1,3,9-triazafluoren-2-yl)benzoate (“HB”).

[0482] 8.3 400 mg of NaH (suspension) are added to a solution of 3.2 gof “HB” in 50 ml of DMF, the mixture is stirred for 1 hour, 2 ml ofiodomethane are subsequently added, and the mixture is stirred for afurther 1 hour. Conventional work-up gives 3.0 g of methyl4-(4-chloro-9-methyl-9H-1,3,9-triazafluoren-2-yl)benzoate (“HC”).

[0483] 8.4 Analogously to Example 7.6, reaction of 1.5 g of “HC” with3-chloro-4-methoxybenzylamine gives 1.0 g of methyl4-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoate(“HD”), m.p. 205-206°.

[0484] 8.5 Ester hydrolysis of “HD” analogously to Example 7.7 gives4-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0485] Analogous reaction of “HC” with 3,4-methylenedioxybenzylaminefollowed by ester hydrolysis gives

[0486]4-[4-(3,4-methylenedioxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0487] Analogous reaction of “GB” with methyl 5-formylpentanoate,chlorination, methylation, reaction with 3-chloro-4-methoxybenzylamineand ester hydrolysis gives

[0488]5-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]pentanoicacid, potassium salt.

[0489] Analogous reaction of “HB” with benzyl bromide, reaction with3-chloro-4-methoxybenzylamine followed by ester hydrolysis gives

[0490]4-[4-(3-chloro-4-methoxybenzylamino)-9-benzyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0491] Analogous reaction of “HB” with 2-iodopropane, reaction with3-chloro-4-methoxybenzylamine followed by ester hydrolysis gives

[0492]4-[4-(3-chloro-4-methoxybenzylamino)-9-isopropyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid, sodium salt, m.p.>250°.

[0493] The examples below relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

[0494] A solution of 100 g of an active ingredient of the formula I and5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

[0495] A mixture of 20 g of an active ingredient of the formula I ismelted with 100 g of soya lecithin and 1400 g of cocoa butter, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

[0496] A solution is prepared from 1 g of an active ingredient of theformula I 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

[0497] 500 mg of an active ingredient of the formula I are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

[0498] A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

[0499] Tablets are pressed analogously to Example E and subsequentlycoated in a conventional manner with a coating of sucrose, potatostarch, talc, tragacanth and dye.

EXAMPLE G Capsules

[0500] 2 kg of active ingredient of the formula I are introduced in aconventional manner into hard gelatine capsules in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

[0501] A solution of 1 kg of active ingredient of the formula I in 60 lof bidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation Spray

[0502] 14 g of active ingredient of the formula I are dissolved in 10 lof isotonic NaCl solution, and the solution is transferred intocommercially available spray containers with pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1. Compounds of the formula I

in which R¹ and R² are each, independently of one another, H, A, OH, OAor Hal, R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, R³ and R⁴are each, independently of one another, H, A or Hal, R³ and R⁴ togetherare alternatively alkylene or alkylidene having 3-5 carbon atoms, or

W is H or alkyl having 1, 2, 3 or 4 carbon atoms, X is CH or N, Y is(CH₂)_(q)—R⁷ or R⁵, R⁶ or R⁹, each of which is unsubstituted ormonosubstituted by (CH₂)_(n)R²⁰, Z is O, NH or NA′, A′ is alkyl having1-6 carbon atoms, —CHAr or —CHAr-A″, A″ is alkyl having 1-6 carbonatoms, R⁵ is linear or branched alkyl having 1-10 carbon atoms, in whichone or two CH₂ groups may be replaced by —CH═CH— groups, —C≡C— groups,—O—, CO, —S—, —SO—, SO₂, —NH— or —NA—, R⁶ is cycloalkyl orcycloalkylalkylene having 5-12 carbon atoms, R⁷ is a saturated orunsaturated 5-7-membered heterocyclic radical having 1-4 N, O or S atomswhich is unsubstituted or monosubstituted, disubstituted ortrisubstituted by R²⁰, A, Hal or CF₃, R⁹ is Ar or (CH₂)_(k)—Ar, R¹⁰,R¹¹, R¹² and R¹³ are each, independently of one another, H, A, Hal, OA,OH, NH₂, NHA, NA₂ or R²⁰, R²⁰ is —COOH, —COOA, —CONH₂, —CONHA, —CONA₂,—CN, tetrazol-5-yl, —S(O)_(m)A, —S(O)_(m)NH₂ or —S(O)_(m)OH,

A is alkyl or alkenyl having from 1 to 6 carbon atoms, in which 1-7 Hatoms may be replaced by F, Ar is a phenyl radical which isunsubstituted or monosubstituted, disubstituted or trisubstituted byHal, A, OA, OH, SO₂NH₂, SO₂NHA, SO₂NA₂ or CN, Hal is F, Cl, Br or I, kand q are each, independently of one another, 0, 1, 2, 3 or 4, m is 1 or2 and n is 0, 1, 2 or 3, and pharmaceutically usable derivates, solvatesand stereoisomers, thereofincluding mixtures thereof in all ratios. 2.Compounds according to claim 1, wherein X is CH, and pharmaceuticallyusable derivatives, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 3. Compounds according to claim 1,wherein R⁹ is a phenyl radical which is unsubstituted or monosubstitutedor disubstituted by COOH, COOA, CONH₂, CONA₂, CONHA, CN, NHSO₂A,N(SO₂A)₂ or SO₂A, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds according to claim 1, wherein Y is phenyl, 1-piperidinyl,piperazinyl or cyclohexyl, each of which is monosubstituted ordisubstituted by COOH, COOA or —S(O)_(m)A, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 5. Compounds according to claim 1, wherein R³ andR⁴ are each, independently of one another, H, A, OA or Hal, R¹ and R²together are —O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O, Y is phenyl,1-piperidinyl, piperazinyl or cyclohexyl, each of which ismonosubstituted or disubstituted by COOH, COOA or —S(O)_(m)A, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 6. Compounds according toclaim 1, wherein R³ and R⁴ together are —(CH₂)₃—, —(CH₂)₄— or—CH═CH—CH═CH—, R¹ and R² are each, independently of one another, H, OAor Hal, R¹ and R² together are alternatively alkylene containing—CH₂—O—CH₂—, Y is phenyl, 1-piperidinyl, piperazinyl or cyclohexyl, eachof which is monosubstituted or disubstituted by COOH, COOA or—S(O)_(m)A, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 7.Compounds according to claim 1, wherein Y is cyclopentylmethylene,cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene orcyclohexylbutylene, each of which is monosubstituted by COOH or COOA,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 8. Compoundsaccording to claim 1, wherein Y is R ⁵or R⁶, each of which issubstituted by COOH, COOA, CONH₂, CONA₂, CONHA or —S(O)_(m)A, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 9. Compounds according toclaim 1, wherein Y is R⁵, R⁶ or R⁹, each of which is substituted by—(CH₂)_(n)—R²⁰, R⁵ is methyl, ethyl, propyl or butyl, R⁹ is phenyl orbenzyl, n is 0 or 1 R²⁰ is COOH, COOA, CONH₂, CONA₂, CONHA or—S(O)_(m)A, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 10.Compounds according to claim 1, wherein X is CH, Y is R⁵, R⁶ or R⁹, eachof which is substituted by —(CH₂)_(n)—R²⁰, R⁵ is methyl, ethyl, propylor butyl, R⁹ is phenyl or benzyl, n is 0 or 1, R²⁰ is COOH or COOA, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 11. Compounds according toclaim 1, wherein X is CH, Y is R⁵, R⁶ or R⁹, each of which issubstituted by —(CH₂)_(n)—R²⁰, Z is NH or NHA′, R⁵ is methyl, ethyl,propyl or butyl, R⁹ is phenyl or benzyl, n is 0 or 1, R²⁰ is COOH orCOOA, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 12.Compounds according to claim 1, wherein X is CH, Y is R⁵, R⁶ or R⁹, eachof which is substituted by —(CH₂)_(n)—R²⁰, Z is O, R⁵ is methyl, ethyl,propyl or butyl, R⁹ is phenyl or benzyl, n is 0 or 1, R²⁰ is COOH orCOOA, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 13.Compounds according to claim 1, wherein X is CH, Y is R⁵, R⁶ or R⁹, eachof which is substituted by —(CH₂)_(n)—R²⁰, Z is NH or NHA′, R³ and R⁴together are alkylene having 3-4 carbon atoms, R⁵ is methyl, ethyl,propyl or butyl, R⁹ is phenyl or benzyl, n is 0 or 1, R²⁰ is COOH orCOOA; and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 14.Compounds according to claim 1, wherein X is CH, Y is R⁵, R⁶ or R⁹, eachof which is substituted by —(CH₂)_(n)—R²⁰, Z is O, R³ and R⁴ togetherare alkylene having 3-4 carbon atoms, R⁵ is methyl, ethyl, propyl orbutyl, R⁹ is phenyl or benzyl, n is 0 or 1, R²⁰ is COOH or COOA, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 15. Compounds according toclaim 1, wherein R¹ and R² are each, independently of one another, H, A,OH, OA or Hal, R¹ and R² together are alternatively alkylene having 3-5carbon atoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, R³and R⁴ are each, independently of one another, H, A or Hal, R³ and R⁴together are alternatively alkylene or alkylidene having 3-5 carbonatoms, or

W is H, X is CH or N, Y is (CH₂)_(q)—R⁷, or R⁵, R⁶ or R⁹, each of whichis unsubstituted or monosubstituted by (CH₂)_(n)R²⁰, Z is O, NH or NA′,A′ is alkyl having 1-6 carbon atoms, —CHAr or —CHAr-A″, A″ is alkylhaving 1-6 carbon atoms, R⁵ is linear or branched alkyl having 1-10carbon atoms, R⁶ is cycloalkyl or cycloalkylalkylene having 5-12 carbonatoms, R⁷ is a saturated or unsaturated, 5-7-membered heterocyclicradical having 1-2 N atoms which is unsubstituted or monosubstituted byR²⁰, A, Hal or CF₃, R⁹ is Ar or (CH₂)_(k)—Ar, R¹⁰, R¹¹, R¹² and R¹³ areH, R²⁰ is —COOH, —COOA or —S(O)_(m)A, A is alkyl having from 1 to 6carbon atoms, in which 1-7 H atoms may be replaced by F, Ar is phenyl,Hal is F, Cl, Br or I k and q are each, independently of one another, 0,1, 2, 3 or 4, m is 1 or 2 and n is 0, 1, 2 or 3, and pharmaceuticallyusable derivatives, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 16. Compounds of the formula I accordingto claim 1,4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-benzylamino-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3,4-dimethoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3,4-dichlorobenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3,4-methylenedioxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-benzylamino-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-(3,4-dimethoxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-(3,4-dichlorobenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-(3,4-methylenedioxybenzylamino)-9-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid,4-(4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl)benzoicacid,4-[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid,4-[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]benzoicacid,4-{4-[(pyridin-3-ylmethyl)amino]-5,6,7,8-tetrahydrobenzo[4,5]-furo[2,3-d]pyrimidin-2-yl}benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]butyricacid,4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-yl]butyricacid,1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperidine-4-carboxylicacid,1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]piperazine,1-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]furo[2,3-d]pyrimidin-2-ylmethyl]-4-methylsulfonylpiperazine,4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]butyricacid,4-[4-(3-chloro-4-methoxybenzylamino)-9H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3,4-methylenedioxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-9-ethyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3,4-methylenedioxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid,5-[4-(3-chloro-4-methoxybenzylamino)-9-methyl-9H-1,3,9-triazafluoren-2-yl]pentanoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-9-benzyl-9H-1,3,9-triazafluoren-2-yl]benzoicacid,4-[4-(3-chloro-4-methoxybenzylamino)-9-isopropyl-9H-1,3,9-triazafluoren-2-tl]benzoicacid, and pharmaceutically usable derivatives, solvates andstereoisomers thereof.
 17. Process for the preparation of compounds ofthe formula I according to claim 1 and salts thereof, characterised inthat a) a compound of the formula II

in which Y, Z, R¹ and R² are as defined in claim 1, and L is Cl, Br, OH,SCH₃ or a reactive esterified OH group, is reacted with a compound ofthe formula III

in which X, W, R¹ and R² are as defined in claim 1, or b) a radical X ina compound of the formula I is converted into another radical X by, forexample, hydrolysing an ester group to give a COOH group or converting aCOOH group into an amide or a cyano group, and/or in that a compound ofthe formula I is converted into one of its salts.
 18. Compounds of theformula I according to claim 1 as inhibitors of phosphodiesterase V. 19.Medicament comprising at least one compound of the formula I accordingto claim 1 and/or pharmaceutically acceptable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and, ifdesired, excipients and adjuvants.
 20. Use of compounds according to oneor more of claims 1 to 16 claim 1 and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment of angina, high blood pressure, pulmonary hypertension,congestive heart failure, cardiac infarction, chronic obstructivepulmonary disease (COPD), cor pulmonale, dextrocardiac insufficiency,atherosclerosis, conditions of reduced patency of the heart vessels,peripheral vascular diseases, strokes, bronchitis, allergic asthma,chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome,tumours, renal insufficiency, liver cirrhosis, for the treatment offemale sexual disorders, inflammation, osteoporosis, for the treatmentof malign hypertonia, phaeochromacytoma, peripheral vascular (occlusion)diseases, vascular diseases, thrombocytopenia, ulcus pepticum,peristaltic motion disorders, percutaneous transluminal coronaryangioplasty, carotid angioplasty, postoperative stenosis of the coronarybypass, premonitory pains and benign prostate hyperplasia.
 21. Use ofcompounds according to claim 1 and/or physiologically acceptable saltsand solvates thereof for the preparation of a medicament for thetreatment of diseases of the cardiovascular system and for the treatmentand/or therapy of potency disorders.
 22. Medicament comprising at leastone compound of the formula I according to claim 1 and/orpharmaceutically acceptable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient.
 23. Medicament comprising at leastone compound of the formula I according to claim 1 and/orpharmaceutically acceptable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient selected from the group consistingof a) prostaglandin or prostaglandin derivative, b) calcium antagonist,c) antithrombotic, d) endothelin receptor antagonist, e) nitrate, f)α-adrenergic inhibitor, g) centrally acting dopaminergic activeingredient, h) ACE inhibitor, i) NEP inhibitor, j) mixed α,β-inhibitor,k) vasoactive intestinal peptide.
 24. Set (kit) consisting of separatepacks of (a) an effective amount of a compound of the formula Iaccording to claim 1 and/or pharmaceutically acceptable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and (b) an effective amount of a further medicament activeingredient.
 25. Use of compounds of the formula I according to claim 1and/or pharmaceutically acceptable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of diseases of thecardiovascular system, for the treatment and/or therapy of potencydisorders, for the treatment of angina, high blood pressure, pulmonaryhypertension, congestive heart failure, cardiac infarction, chronicobstructive pulmonary disease (COPD), cor pulmonale, dextrocardiacinsufficiency, atherosclerosis, conditions of reduced patency of theheart vessels, peripheral vascular diseases, strokes, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritablebowel syndrome, tumours, renal insufficiency, liver cirrhosis, for thetreatment of female sexual disorders, inflammation, osteoporosis, forthe treatment of malign hypertonia, phaeochromacytoma, peripheralvascular (occlusion) diseases, vascular diseases, thrombocytopenia,ulcus pepticum, peristaltic motion disorders, percutaneous transluminalcoronary angioplasty, carotid angioplasty, postoperative stenosis of thecoronary bypass, premonitory pains and benign prostate hyperplasia, incombination with at least one further medicament active ingredient. 26.Intermediates of the formula II

in which Y, Z, R³ and R⁴ are as defined in claim 1, and L is Cl, Br, OH,SCH₃ or a reactive esterified OH group, and salts thereof.